2,4-Disubstituted-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrenes

ABSTRACT

2,4-Disubstituted-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrenes e.g., 2,4-dimethoxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene are useful as hypolipidemic agents.

This a division of application Ser. No. 637,718 filed Dec. 4, 1975 nowU.S. Pat. No. 4,034,045 which is turn is a continuation-in-part ofcopending application Serial No. 556,759 filed April 10, 1975, nowabandoned which in turn is a continuation of application Serial No.368,939 filed June 11, 1973, now abandoned.

This invention relates to 2,4-substituted-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene derivatives, intermediates andprocesses for their preparation and their use as hypolipidemic agents.The compounds of this invention may be represented by the followingstructural formula: ##STR1## where R represents hydrogen, or loweralkyl, i.e. alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl,isopropyl and the like.

The compounds of formula (I) in which R is lower alkyl may be preparedby the following reaction scheme: ##STR2## where X is a leaving groupsuch as chloride, bromide, iodide, methyl sulfate or sulfate, preferablyiodide, methyl sulfate or sulfate, and

R' is lower alkyl as defined above.

The compounds of formula (I') are prepared by treating the compound ofthe formula (II) with a compound of the formula (III) under an inertatmosphere such as argon, neon, nitrogen and the like, preferablynitrogen, in the presence of an acid binding agent and an inertnon-aqueous solvent. The particular acid binding agent employed is notcritical, although it is preferred that the reaction be carried out inthe presence of an inorganic acid binding agent, such as an alkali metalcarbonate, e.g. potassium carbonate, sodium carbonate or lithiumcarbonate, an alkali metal hydride, e.g. sodium hydride, potassiumhydride and the like, an alkali metal hydroxide, e.g. sodium hydroxide,potassium hydroxide and the like, or an alkali earth metal hydride, e.g.calcium hydride, especially preferred is potassium carbonate. The acidbinding agent employed may also be an organic acid binding agent such asa tertiary amine, e.g. triethylamine. The particular non-aqueous solventused is not critical, but it is preferred that the reaction be run inthe presence of dioxane, tetrahydrofuran, or acetone, the latter beingespecially preferred. The temperature of the reaction is not critical,but it is preferred that the reaction be carried out between 0° and 150°C., especially the reflux temperature of the solvent. The reaction isrun from about 1 to 50 hours, preferably from about 16 to 28 hours. Theproduct is recovered using conventional techniques e.g.recrystallization.

The compounds of formula (II) are prepared by the following reactionscheme: ##STR3##

The compounds of formula (II) are prepared by treating1-acetylcyclohexene (IV) with phloroglucinol (V) under an inertatmosphere such as argon, neon, nitrogen and the like, preferablynitrogen in the presence of both a strong base and an alcoholic solvent.Although the particular strong base employed is not critical, it ispreferred that the reaction be run in the presence of an alkali metalhydroxide such as potassium hydroxide, sodium hydroxide and the like, analkali metal alkoxide, such as sodium methoxide, potassium methoxide,sodium ethoxide and the like, or an alkali metal hydride such as sodiumhydride, potassium hydride and the like, preferably potassium hydroxide.The particular solvent employed is critical and must be an alcoholicsolvent such as an alkoxy alcohol, e.g., 2-methoxyethanol,2-ethoxyethanol and the like, a lower alkanol such as methanol, ethanol,propanol, n-butanol and the like, or an ether of ethylene glycol such asmethylether or ethylether, preferably 2-methoxyethanol. The temperatureof the reaction is not critical, but it is preferred that the reactionbe run at temperatures from about 50 to 150° C., especially the refluxtemperature of the solvent. The reaction is run from 1 to 40 hours,preferably 3 to 6 hours. The compounds of formula (II) are recoveredusing conventional techniques, e.g. acidification followed byrecrystallization.

The compounds of formulae (IV) and (V) are known and may be prepared bymethods disclosed in the literature.

The compounds of formula (I') are useful because they possesspharmacological activity in animals as hypolipidemic agents, asindicated by the fall of cholesterol and triglyceride levels in malealbino Wistar rats weighing 110 to 130 g. initially. The rats aremaintained on drug-free laboratory chow diets for seven days and thendivided into groups of 8 to 10 animals. Each group, with the execeptionof the control, is then given orally 30 milligrams per kilogram of bodyweight per diem of the compound for six days. At the end of this period,the animals are anethetized with sodium hexobarbital and bled from thecarotid arteries. Serum or plasma samples are collected, and 1.0 ml.samples of the serum are added to 9.0 ml. redistilled isopropanol. Twoautoanalyzer cupsful of a mixture of zeolite-copper hydroxide andLloydds reagent (Kessler, E., and Lederer, H., 1965, Technicon SymposiumMediad Inc., New York, 345-347!) are added, and the mixture is shakenfor one hour. Cholesterol and triglyceride levels are determinedsimultaneously on the same sample by Technicon N 24 A (cholesterol) andN-78 (triglyceride) methodology. The mean total serum cholesterol levelsare then computed and the hypocholesterolemic activity is expressed asthe fall in cholesterol levels as a percentage of the control level. Thechange in serum triglyceride levels induced by the drug is computed as apercentage of the control triglyceride levels.

For such usage, the compounds (I') may be combined with apharmaceutically acceptable carrier or adjuvant and may be administeredorally or parenterally as such or admixed with conventionalpharmaceutical carriers. They may be administered in such forms astablets, dispersible powders, granules, capsules, syrups and elixirs andparenterally as solutions, suspensions, dispersions, emulsions and thelike, e.g., a sterile injectable aqueous solution. The dosage will varydepending upon the mode of administration utilized and the particularcompound employed.

The hypolipidemic effective dosage of compounds (I') employed in thealleviation of lipidemia may vary depending on the particular compoundemployed and the severity of the condition being treated. However, ingeneral, satisfactory results are obtained when the compounds of formula(I') are administered at a daily dosage of from about 4.0 milligrams toabout 250 milligrams per kilogram of animal body weight, preferablygiven in divided doses two to four times a day, or in sustained releaseform. For most large mammals, the total daily dosage is from about 300milligrams to about 3000 milligrams. Dosage forms suitable for internaluse comprise from about 75 to 1500 milligrams of the active compound inintimate admixture with a solid or liquid pharmaceutically acceptablecarrier or diluent.

A representative formulation suitable for oral administration 2 to 4times a day for the treatment of lipidemia is a capsule prepared bystandard encapsulating techniques which contains the following:

    ______________________________________                                        Ingredients           Weight (mg.)                                            ______________________________________                                        2,4-dimethoxy-4b,5,6,7,8,8a,9,10-                                             octahydro-9-oxo-phenanthrene                                                                        150                                                     inert solid diluent (starch,                                                  lactose, kaolin).     300                                                     ______________________________________                                    

EXAMPLE I 2,4-Dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene

To a flask equipped with a stirrer, dropping funnel, condenser and gasinlet tube maintained under a nitrogen atmosphere, there is added 50 g.(0.89) moles of potassium hydroxide in one liter of 2-methoxyethanol.Stirring is initiated and 100 g. (0.79 mole) of anhydrous phloroglucinolis added in three portions, followed by the addition of 100 g. (0.80mole) of 1-acetyl-cyclohexene while maintaining the temperature at 50°C. The resulting solution is refluxed at 140° C. for 4 hours. Aftercooling there is then added gradually 53.6 g. of acetic acid whileobtaining a pH of approximately 7. The solvent is then removed in vacuo,and the residue is further heated in an oil bath at 70° C., to obtain aviscous residue. The resulting residue is dissolved in ethyl acetate andwater washed twice with water, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to obtain a brown solid. The resultingsolid is recrystallized from ethyl acetate/cyclohexane to give2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene; m.p.220°-223° C.

EXAMPLE II 2,4-Dimethoxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene

To a flask equipped with a stirrer, dropping funnel, condenser, and gasinlet tube maintained under a nitrogen atmosphere, there is added 23.2g. (0.1 mole) of2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene, 20 g.(0.15 mole) of dimethyl sulfate, 22 g. (0.16 mole) of dry potassiumcarbonate and 500 ml. of dry acetone, the resulting mixture is thenrefluxed with stirring overnight. The resulting suspension is cooled, 5ml. of water is added and stirring is continued for an additional 5minutes. The mixture is filtered, and the filtrate is concentrated todryness. The resulting residue is recrystallized from acetone/methanolto give 2,4-dimethoxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene;m.p. 130°-131° C.

What is claimed is:
 1. A compound of the formula ##STR4## where Rrepresents hydrogen or lower alkyl having 1 to 4 carbon atoms.
 2. Thecompound of claim 1 which is2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene.
 3. Thecompound of claim 1 which is2,4-dimethoxy-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrene.
 4. Apharmaceutical composition for use in the treatment of lipidemia whichcomprises a hypolipidemically effective amount of a compound of claim 1and a pharmaceutically acceptable diluent or carrier therefor.
 5. Amethod of treating lipidemia which comprises administering to a mammalin need of said treatment of hypolipidemic effective amount of acompound of claim 1.